The microbial communities living within our bodies help us resist acute infection, regulate our immune responses, and play important roles in our nutrition and metabolism. Unlike our own cells, our microbial passengers can be genetically modified or replaced without risking cancer or immune rejection. Despite these advantages, very few tools capable of making precise or lasting changes to our internal ecosystems are available. Reliable methods of controlling the composition of these communities could open the door to a new medicinal paradigm focused on immunizing microbes against pathogenesis and harnessing them as living therapeutics.
Numerically, humankind is more microbial than human. Our bodies are comprised of ˜1013 human cells and ˜1014 microbes (Ley et al. Cell 2006 February; 124(4):837-848; Qin et al. Nature 2010 March; 464(7285):59-65). The composition of these microbial communities, collectively termed the microbiota, has a commensurately dramatic impact on human health and disease (Lawley et al. Immunology 2013 January; 138(1):1-11; Lozupone et al. Nature 2012 September; 489(7415):220-230. Healthy and diverse microbial communities prevent pathogens from invading our bodies by competing for space and nutrients (Leatham et al. Infect. Immun. 2009 July; 77(7):2876-2886; Kamada et al. Nat. Immunol. 2013 July; 14(7):685-690) and clearing existing infections (Barman et al. Infect. Immun. 2008 March; 76(3):907-915; Endt et al. PLoS Pathog. 2010; 6(9):e1001097). The composition of the microbiota is an equally strong determinant of chronic disorders, from H. pylori-induced gastric disease (Marshall et al. Lancet 1984 June; 1(8390):1311-1315; Salama et al. Nat. Rev. Microbiol. 2013 June; 11(6):385-399) to obesity (Turnbaugh et al. Nature 2006 December; 444(7122):1027-1031; Ridaura et al. Science 2013 September; 341(6150):1241214) metabolic syndrome (Vrieze et al. Gastroenterology 2012 October; 143(4):913-916.e7), and the complexities of inflammatory bowel disease (Kamada, Supra; Abraham et al. Gastroenterology 2011 May; 140(6):1729-1737; Horwitz et al. Inflamm. Bowel Dis. 2007 April; 13(4):490-500). Even the dramatic metabolic benefits conferred by gastric bypass surgery may be largely due to changes in the microbiota (Liou et al. Sci Transl Med 2013 March; 5(178):178ra41).
Much of our newfound knowledge stems from the herculean efforts of researchers involved in the Human Microbiome Project and MetaHIT. These major initiatives and related studies employing metagenomic sequencing to paint comprehensive portraits of the genes and species involved in health and disease (Human Microbiome Project Consortium. A framework for human microbiome research. Nature 2012 June; 486(7402):215-221; Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012 June; 486(7402):207-214; Turnbaugh et al. Sci Transl Med 2009 November; 1(6):6ra14; Le Chatelier et al. Nature 2013 August; 500(7464):541-546; Cotillard et al. Nature 2013 August; 500(7464):585-588).
Unfortunately, there has been no comparable effort to develop interventions capable of altering pictures of disease to ones of health. Antibiotics, fecal transplantation, and dietary changes are all highly effective treatments for various gastric conditions (Vrieze, Supra; Estruch et al. N. Engl. J. Med. 2013 April; 368(14):1279-1290; Smoot et al. Am. J. Gastroenterol. 1999 April; 94(4):955-958; Pimentel et al. Am. J. Gastroenterol. 2000 December; 95(12):3503-3506; Van Nood et al. N. Engl. J. Med. 2013 January; 368(5):407-415), but using them to make precise changes to the microbiota is tantamount to sculpting a forest with fire (Lozupone, Supra). Antibiotics typically result in losses of community diversity and stability that may cause disease (Larson et al. Lancet 1978 May; 1(8073):1063-1066; Cho et al. Nature 2012 August; 488(7413):621-626) and can be permanent (Dethlefsen et al. PLoS Biol. 2008 November; 6(11):e280; Antonopoulos et al. Infect. Immun. 2009 June; 77(6):2367-2375); in these cases, transplanting the microbiota of a healthy donor cannot restore these losses (Manichanh et al. Genome Res. 2010 October; 20(10):1411-1419) as transplanted communities typically revert to that of the recipient (McNulty et al. Sci Transl Med 2011 October; 3(106):106ra106; Nieuwdorp Gastroenterology 2013 April; 144(4):e20-21) except when the latter is effectively eliminated (Van Nood, Supra). Similarly, ingesting beneficial probiotic species is analogous to scattering apple seeds in the woods, as introduced species are normally eliminated from the gut due to colonization resistance by existing species that already occupy all available ecological niches (McNulty, Supra; Lee et al. Nature 2013 September; 501(7467):426-429; Maltby et al. PLoS ONE 2013; 8(1):e53957).
The absence of methods allowing the cellular and genetic composition of the microbiota to be stably altered has severely impaired mankind's scientific understanding. Even as the ability to knock out and overexpress individual genes has transformed knowledge of cellular complexity and function, developing equivalent capabilities for manipulating the genes and species of the microbiota will be essential to unraveling the still greater complexity of our internal ecosystems.
To sculpt the microbiota, the evolutionary fitness of individual genes and species must be controlled. Phages and mobile genetic parasites might be similarly harnessed to engineer populations of bacteria. Phage predation is both highly specific to individual species and of great ecological importance (Abedon, ST. Bacteriophage ecology: population growth, evolution, and impact of bacterial viruses. Cambridge: Cambridge University Press; 2008), with a long history of therapeutic use against pathogenic bacteria in Eastern Europe (Abedon Bacteriophage 2011; 1(2):66-85) and a low bar for FDA approval (Brussow Virology 2012 December; 434(2):138-142). Similarly, mobile genetic elements are known to readily spread through the microbiota (Stecher et al. Proc. Natl. Acad. Sci. U.S.A. 2012 January; 109(4):1269-1274) and have been proposed as vehicles to deliver lethal genes (Filutowicz et al. Plasmid 2008 July; 60(1):38-44; Fairhead Drug News Perspect. 2009 May; 22(4):197-203).
Editing the genomes of native species or replacing them with protective strains could immunize microbial ecosystems against dysbiosis, antibiotic resistance, and pathogenicity. Stable populations of engineered cells could secrete consistent levels of therapeutic and regulatory molecules for the in situ treatment of disease.